TY - JOUR
T1 - Quantifying single-cell ERK dynamics in colorectal cancer organoids reveals EGFR as an amplifier of oncogenic MAPK pathway signalling
AU - Ponsioen, Bas
AU - Post, Jasmin B.
AU - Buissant des Amorie, Julian R.
AU - Laskaris, Dimitrios
AU - van Ineveld, Ravian L.
AU - Kersten, Simone
AU - Bertotti, Andrea
AU - Sassi, Francesco
AU - Sipieter, François
AU - Cappe, Benjamin
AU - Mertens, Sander
AU - Verlaan-Klink, Ingrid
AU - Boj, Sylvia F.
AU - Vries, Rob G.J.
AU - Rehmann, Holger
AU - Vandenabeele, Peter
AU - Riquet, Franck B.
AU - Trusolino, Livio
AU - Bos, Johannes L.
AU - Snippert, Hugo J.G.
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/4
Y1 - 2021/4
N2 - Direct targeting of the downstream mitogen-activated protein kinase (MAPK) pathway to suppress extracellular-regulated kinase (ERK) activation in KRAS and BRAF mutant colorectal cancer (CRC) has proven clinically unsuccessful, but promising results have been obtained with combination therapies including epidermal growth factor receptor (EGFR) inhibition. To elucidate the interplay between EGF signalling and ERK activation in tumours, we used patient-derived organoids (PDOs) from KRAS and BRAF mutant CRCs. PDOs resemble in vivo tumours, model treatment response and are compatible with live-cell microscopy. We established real-time, quantitative drug response assessment in PDOs with single-cell resolution, using our improved fluorescence resonance energy transfer (FRET)-based ERK biosensor EKAREN5. We show that oncogene-driven signalling is strikingly limited without EGFR activity and insufficient to sustain full proliferative potential. In PDOs and in vivo, upstream EGFR activity rigorously amplifies signal transduction efficiency in KRAS or BRAF mutant MAPK pathways. Our data provide a mechanistic understanding of the effectivity of EGFR inhibitors within combination therapies against KRAS and BRAF mutant CRC.
AB - Direct targeting of the downstream mitogen-activated protein kinase (MAPK) pathway to suppress extracellular-regulated kinase (ERK) activation in KRAS and BRAF mutant colorectal cancer (CRC) has proven clinically unsuccessful, but promising results have been obtained with combination therapies including epidermal growth factor receptor (EGFR) inhibition. To elucidate the interplay between EGF signalling and ERK activation in tumours, we used patient-derived organoids (PDOs) from KRAS and BRAF mutant CRCs. PDOs resemble in vivo tumours, model treatment response and are compatible with live-cell microscopy. We established real-time, quantitative drug response assessment in PDOs with single-cell resolution, using our improved fluorescence resonance energy transfer (FRET)-based ERK biosensor EKAREN5. We show that oncogene-driven signalling is strikingly limited without EGFR activity and insufficient to sustain full proliferative potential. In PDOs and in vivo, upstream EGFR activity rigorously amplifies signal transduction efficiency in KRAS or BRAF mutant MAPK pathways. Our data provide a mechanistic understanding of the effectivity of EGFR inhibitors within combination therapies against KRAS and BRAF mutant CRC.
UR - http://www.scopus.com/inward/record.url?scp=85103594994&partnerID=8YFLogxK
U2 - 10.1038/s41556-021-00654-5
DO - 10.1038/s41556-021-00654-5
M3 - Article
C2 - 33795873
AN - SCOPUS:85103594994
VL - 23
SP - 377
EP - 390
JO - Nature Cell Biology
JF - Nature Cell Biology
SN - 1465-7392
IS - 4
ER -